Pathological neovascularization is a key component of diseases like wet age-related macular degeneration (AMD), proliferative diabetic retinopathy, rheumatoid arthritis, osteoarthritis, and asthma. It also plays an important role in growth and spread of tumors. Neovascularization is regulated by an exquisite balance of pro- and anti-angiogenic factors.
Vascular endothelial growth factor (VEGF) is known to be necessary for neovascularization. Inhibition of VEGF activity has been shown to inhibit neovascularization in animal models of AMD, arthritis and in various tumor models. Methods used to inhibit VEGF activity include antibodies, receptor fusion proteins, peptides and small molecules.
VEGF-R1 (Flt-1) and VEGF-R2 (KDR) proteins have been shown to bind VEGF with high affinity. Both Flt-1 and KDR have seven Ig-like domains in their extracellular region. Domain 2 has been shown to be essential for VEGF binding. Fusions of each of the full-length, soluble receptor (domains 1-7) and domains 1-3 to IgG Fc bind VEGF efficiently. IgG Fc fusions to Ig-like domain 2 alone was, however, incapable of binding VEGF, as was a combination of Ig-like domain 1 and 2. Davis-Smyth, 1996. Therefore, Ig-like domains 1 and 3 seem to be required along with domain 2 for efficient VEGF binding.